The present invention relates to active constituent salts and esters of 1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol and 3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl)-phenol, processes for their production, their use for the production of a medicament for the treatment of increased urinary urgency and urinary incontinence, as well as corresponding medicaments and processes for the treatment of increased urinary urgency, urinary incontinence and pain.
Urinary incontinence is the involuntary voiding of urine. This occurs in an uncontrolled manner if the pressure within the bladder exceeds the pressure that is necessary to close the ureter. Causes may include on the one hand an increased internal bladder pressure (for example due to detrusor instability) resulting in urgency incontinence, and on the other hand a reduced sphincter pressure (for example after childbirth or surgical intervention), resulting in stress incontinence. The detrusor is the collective term for the coarse bundles of multilayer muscles of the bladder wall, whose contraction leads to release of urine; the sphincter is the constrictor muscle of the urethra. Mixed forms of these types of incontinence as well as so-called overflow incontinence (e.g. in benign prostatic hyperplasia) or reflex incontinence (e.g. after spinal cord injury) occur. Further details can be found in Chutka, D. S. and Takahashi, P. Y., 1998, Drugs 560: 587-595.
Urinary urgency is the state of increased bladder muscle tension leading to voiding of urine (micturition) when the bladder is almost full (or when its capacity is exceeded). This muscle tension acts as a stimulus to pass urine. Increased urinary urgency is understood in this connection to mean in particular the occurrence of premature or more frequent and sometimes even painful urinary urgency up to so-called dysuria. This consequently leads to a significantly increased frequency of micturition. Causes may include, inter alia, inflammation of the bladder and neurogenic bladder disorders, as well as also bladder tuberculosis. However, all causes have not yet been elucidated.
Increased urinary urgency and also urinary incontinence are regarded as extremely unpleasant and there is therefore a clear need to achieve the greatest possible long-term improvement in patients affected by these medical conditions.
Increased urinary urgency and in particular urinary incontinence are normally treated with substances that act on the reflexes of the lower urinary tract (Wein A. J., 1998, Urology 51 (Suppl. 21): 43-47). In general these are medicaments that have a blocking effect on the detrusor muscle, which is responsible for the internal bladder pressure. These medicaments include for example parasympatholytics such as oxybutynin, propiverine or tolterodine, tricyclic antidepressants such as imipramine, or muscle relaxants such as flavoxate. Other medicaments that in particular increase the resistance of the urethra or cervix of the bladder have similarities with α-adrenoreceptors such as ephedrine, with β-adrenoreceptors such as clenbutarol, or are hormones such as oestradiol.
A detailed insight into the drugs and therapeutic methods that are used, especially as regards the anti-muscarinics and other peripherally acting substances, is given in the review article by K. E. Andersson et al. “The pharmacological treatment of urinary incontinence”, BJU International (1999), 84, 923-947.
Certain diarylmethylpiperazines and diarylmethylpiperidines are also described in WO 93/15062 for this medical condition. Likewise Tramadol was shown to have a positive effect on bladder function in a rat model of rhythmic bladder contractions (Nippon-Shinyaku, WO 98/46216). Furthermore the relevant literature contains details of investigations on the characterisation of the opioid side effect of urinary retention, from which information has been obtained on the influencing of bladder functions by weak opioids such as diphenoxylate (Fowler et al., 1987 J. Urol. 138: 735-738) and meperidine (Doyle and Briscoe, 1976 Br. J. Urol. 48: 329-335), by mixed opioid agonists/antagonists such as buprenorphine (Malinovsky et al., 1998 Anesth. Analg. 87; 456-461; Drenger and Magora, 1989 Anesth. Analg. 69: 348-353), pentazocine (Shimizu et al. (2000) Br. J. Pharmacol. 131 (3): 610-616) and nalbuphine (Malinovsky et al., 1998, loc. cit.), as well as by powerful opioids such as morphine (Malinovsky et al., 1998, loc. cit.; Kontani and Kawabata, (1988); Jpn. J. Pharmacol. Sept.; 48(1): 31) and fentanyl (Malinovsky et al., 1998, loc. cit.). However, these investigations were generally carried out in analgesically effective concentrations.
It should be noted that treating the medical conditions of interest here involves the very long-term use of medicaments and, in contrast to many situations in which analgesics are used, patients suffer very unpleasant but not intolerable discomfort. Accordingly in this case—even more than with analgesics—care should be taken to avoid side effects if the patient does not wish to exchange one discomfort for another. Furthermore, in the long-term treatment of urinary incontinence analgesic effects are also largely undesirable.